Colorectal cancer (CRC) is the second leading cause of cancer-related death and the third most common cancer in the US. Inflammation is a key contributor to carcinogenesis, and there is an increased incidence of cancer in patients with chronic inflammatory diseases. Inflammation in the tumor microenvironment can enhance cancer cell proliferation, survival, and migration. A chronically inflamed colonic mucosa is pro- neoplastic;and ulcerative colitis (UC) is one of the highest risk factors for the development of CRC. Recent data suggest that immune responses to commensal gut bacteria may influence the development of CRC and colitis-associated colorectal cancer (caCRC). However, how the gut microbiota shapes mucosal immune responses leading to chronic inflammation and CRC is not well understood. Important questions include: (1) what are the features of the gut microbiota that elicit chronic inflammatory responses that drive caCRC and (2) how do mucosal innate immune subsets function in the evolving tumor microenvironment. This proposal builds on our recent studies of a spontaneous mouse model of UC and caCRC that is driven genetically by T-bet deficiency in the absence of adaptive immunity, and stems from our preliminary data on the microbial communities that instigate colitis.
Our specific aims are to: 1) define the role of fecal microbial community members in initiating the innate immune driven inflammatory cascades that drive caCRC;2) characterize monocyte populations and their recruitment, function, and response to the intestinal microbiota across the colitis r dysplasia r adenocarcinoma transition;and 3) perform a functional genomic analysis of fecal microbial communities across the colitis r dysplasia r adenocarcinoma transition. We employ cell biology, immunology, and microbiology techniques and sequencing technology as experimental tools, in conjunction, with computational methodology capable of integrating these diverse data sets. By analyzing the function of intestinal microbial communities and innate immune subsets in driving pro-neoplastic inflammation, this proposal will advance basic understanding of the contribution of host-microbial interactions to the evolution of a tumor microenvironment. Since we utilize a mouse model that is reminiscent of UC and recapitulates key features of human IBD-associated CRC, we anticipate that our data will be applicable for human disease and for the development of anti-inflammatory host and/or microbe directed therapeutics that will prevent the development and progression of cancer.
Colorectal cancer is the second leading cause of cancer-related death and the third most common cancer in the US;and inflammation is a key contributor to carcinogenesis. Our proposal examines the role of inflammatory cells and gut bacteria in driving cancer in the colon.
|Yan, Jing; Herzog, Jeremy W; Tsang, Kelly et al. (2016) Gut microbiota induce IGF-1 and promote bone formation and growth. Proc Natl Acad Sci U S A 113:E7554-E7563|
|Howitt, Michael R; Lavoie, Sydney; Michaud, Monia et al. (2016) Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 351:1329-33|
|Song, Mingyang; Garrett, Wendy S; Chan, Andrew T (2015) Nutrients, foods, and colorectal cancer prevention. Gastroenterology 148:1244-60.e16|
|Garrett, Wendy S (2015) Cancer and the microbiota. Science 348:80-6|
|BÃ¶rnigen, Daniela; Moon, Yo Sup; Rahnavard, Gholamali et al. (2015) A reproducible approach to high-throughput biological data acquisition and integration. PeerJ 3:e791|
|Chun, Eunyoung; Lavoie, Sydney; Michaud, Monia et al. (2015) CCL2 Promotes Colorectal Carcinogenesis by Enhancing Polymorphonuclear Myeloid-Derived Suppressor Cell Population and Function. Cell Rep 12:244-57|
|Mima, Kosuke; Sukawa, Yasutaka; Nishihara, Reiko et al. (2015) Fusobacterium nucleatum and T Cells in Colorectal Carcinoma. JAMA Oncol 1:653-61|
|Ballal, Sonia A; Veiga, Patrick; Fenn, Kathrin et al. (2015) Host lysozyme-mediated lysis of Lactococcus lactis facilitates delivery of colitis-attenuating superoxide dismutase to inflamed colons. Proc Natl Acad Sci U S A 112:7803-8|
|Gur, Chamutal; Ibrahim, Yara; Isaacson, Batya et al. (2015) Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity 42:344-55|
|Rooks, Michelle G; Veiga, Patrick; Wardwell-Scott, Leslie H et al. (2014) Gut microbiome composition and function in experimental colitis during active disease and treatment-induced remission. ISME J 8:1403-17|
Showing the most recent 10 out of 29 publications